Trodelvy (sacituzumab govitecan-hziy)

Today, novel agents called antibody drug conjugates (ADCs), including enfortumab vedotin (EV) and sacituzumab govitecan (SG), have been approved for la/mUC offering patients treatment options following or instead of traditional chemotherapy...In 2023, EV in combination with pembrolizumab almost doubled progression-free and overall survival versus platinum-based chemotherapy, which led to accelerated FDA approval as first-line treatment for all patients with la/mUC...Finally, a recent cancer agnostic accelerated approval for trastuzumab deruxtecan (T-DXd) in HER2-positive (IHC3+) solid tumors provides another active ADC option for biomarker-selected patients with treatment refractory la/mUC. Several new ADCs are being investigated in urothelial cancer (UC) clinical trials. This review summarizes the clinical studies and real-world data regarding the use of ADCs in UC.

This narrative review explores key predictive factors influencing the efficacy of ADCs, focusing on HER2-targeted therapies, such as trastuzumab emtansine and trastuzumab deruxtecan, as well as sacituzumab govitecan for triple-negative breast cancer. Finally, future perspectives on the sequential use of ADCs and potential combination therapies are highlighted, along with emerging agents targeting alternative antigens like HER3 and LIV-1. Overall, identifying predictive biomarkers and overcoming resistance mechanisms are essential for optimizing the use of ADCs in metastatic breast cancer, thereby improving patient outcomes.

Employing a humanized TROP2 syngeneic TNBC model, we show that TROP2 targeting via hRS7, the antibody component of Sacituzumab govitecan (SG), enhances the anti-PD1 response associated with improved T cell accessibility and effector function...This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed antibody drug conjugates to activate anti-tumor immunity and enhance immunotherapy response.

P2, N=80, Active, not recruiting, Gilead Sciences | Trial completion date: Dec 2024 --> Dec 2025

These data demonstrate the clinical potential of Trop-2-directed therapy in managing heavily pretreated patients with advanced HNSCC.

P1, N=20, Recruiting, Henry Ford Health System | Not yet recruiting --> Recruiting

Additionally, inhibition of translesion DNA synthesis enhances SG and PARP inhibitor (PARPi) sensitivity in PARPi-resistant OC cells. These findings provide mechanistic insights for clinical development of SG in drug-resistant OC.

In NSCLC, therapies such as osimertinib have improved efficacy in treating EGFR-mutant BM, with emerging combinations such as amivantamab and lazertinib offering promising alternatives for patients resistant to frontline therapies. In HER2-positive breast cancer, significant advancements with tucatinib and trastuzumab deruxtecan (T-DXd) have transformed the treatment landscape, achieving improved survival and intracranial control in patients with BM. Similarly, in triple-negative breast cancer (TNBC), novel therapies such as sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) offer new hope for managing BM. For melanoma, the combination of immune checkpoint inhibitors such as nivolumab and ipilimumab has proven effective in enhancing survival for patients with BM, both in BRAF-mutant and wild-type cases...Future research should optimise combination therapies, overcome resistance, and refine treatment sequencing. Continued emphasis on personalized, biomarker-driven approaches offers the potential to further improve outcomes, even for complex cases.

P1/2, N=46, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Oct 2025 --> Apr 2027 | Trial primary completion date: Oct 2024 --> Apr 2026

P2, N=35, Recruiting, National Taiwan University Hospital | Not yet recruiting --> Recruiting | Initiation date: May 2024 --> Aug 2024

Currently, there are three ADCs available for use in breast cancer: trastuzumab emtansine for HER2 positive breast cancer (early stage and metastatic), trastuzumab deruxtecan for HER2 positive and HER2 low breast cancer (metastatic) and sacituzumab govitecan for triple negative and hormone receptor positive (HR +), HER2 negative breast cancer(metastatic). The future of this class of compounds is very exciting. This field is rapidly evolving with new ADCs being investigated and clinical trials looking at the use of known ADCs in earlier stage disease.

Studies evaluating ADCs (trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), MRG002, and RC48-ADC) in patients with HER2-low a/mBC were included. Future studies should focus on bringing ADCs into earlier lines of therapy in this population. This study was registered in PROSPERO (CRD42024452962).

Trophoblast cell-surface antigen 2 (TROP2), a transmembrane receptor expressed in many carcinomas, is a target for novel antibody-drug conjugates such as sacituzumab govitecan...In metastases, the interobserver variability was similar for both methods. Our observations support the application of the HER2 ASCO/CAP guidelines for semi-quantitative evaluation of membranous TROP2 protein expression, as this method strongly correlates with the H-score and is less prone to interobserver variability in post-NAC breast resections. Future studies should investigate the association between the TROP2 membrane score and response to TROP2-targeted therapy.

P2, N=23, Recruiting, University of California, Irvine | Not yet recruiting --> Recruiting

Notably, the efficacy of the hRS7 ATAC®s was superior to that of Trodelvy® with complete tumor eradication in both, refractory pancreatic and triple negative breast cancer xenograft models. In summary, hRS7 ATAC®s represent a highly effective and well-tolerated targeted therapy, and our data support their development for pancreatic cancer and other TROP2-expressing tumors.

Several Trop-2-targeted ADCs, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-DXd), have demonstrated significant antitumor activity in clinical trials for both triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Notably, Trop-2-targeted ADCs have shown promise in reprogramming the tumor microenvironment through multiple signaling pathways, potentially enhancing antitumor immunity. This review aims to provide new insights and research directions for the development of innovative breast cancer therapies, offering potential solutions to improve treatment outcomes and quality of life for breast cancer patients.

The clinical case described concerns a 53-year-old patient with triple-negative disease, metastatic to the skin, fragile, not due to comorbidities, but due to toxicities from previous antiblastic treatments. The patient has no family history of breast cancer and does not have a mutation in the BRCA1/2 genes. In pathological history, only arterial hypertension under medical therapy with nebivolol.

The efficacy results showed a significantly greater clinical benefit with sacituzumab govitecan compared to standard chemotherapy in patients with triple-negative breast cancer. This drug will become a treatment of substantial impact in future treatment guidelines for this type of cancer.

Our systematic review and meta-analysis confirmed that SG confers good clinical activity in certain solid tumor types and was tolerable with minimal adverse events. The potential utility of UGT1A1*28 genotyping in predicting clinical response and outcomes could not be determined due to the limited number of studies with available UGT1A1 genotype data.

P2, N=129, Not yet recruiting, Fundación GECP | Trial completion date: Jun 2031 --> Nov 2031 | Trial primary completion date: Jun 2031 --> Nov 2031

P4, N=25, Completed, Gilead Sciences | Enrolling by invitation --> Completed | N=200 --> 25

P2, N=348, Recruiting, West German Study Group | Not yet recruiting --> Recruiting

P2, N=23, Not yet recruiting, University of California, Irvine

P1/2, N=56, Active, not recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Recruiting --> Active, not recruiting

For the treatment of breast cancer, there are three ADCs approved for breast cancer treatment: Trastuzumab emtansine (T-DM1), Trastuzumab Deruxtecan (T-Dxd) targeting HER-2, and Sacituzumab Govitecan (SG) targeting Trop-2. This review summarizes the efficacy and adverse effects of ADC therapies that have completed or are currently undergoing phase I-III clinical trials. Additionally, it analyzes potential combination strategies to overcome ADC resistance, aiming to provide clinicians with a comprehensive clinical guide to the use of ADCs in breast cancer treatment.

Therapies targeting mutations in this pathway approved in conjunction with endocrine therapy include alpelisib, everolimus and capivasertib...She received nab-paclitaxel/atezolizumab for 4 months, letrozole and abemaciclib for 2 months, letrozole alone for 6 months, and letrozole and ribociclib for 6 weeks. Given presence of PIK3CA mutation, 4th line treatment with fulvestrant and alpelisib was planned...After progressing on capecitabine after 2 months, alpelisib with exemestane was initiated...Due to a low ejection fraction despite work with cardiooncology, she was not a candidate for trastuzumab deruxtecan. She progressed on oral cyclophosphamide and methotrexate after 2 months and Sacituzumab govitecan after 3 months...Comprehensive biomarker assessment is needed to identify patients who may benefit from sequential therapies. There is a need for trials comparing therapies that target the PI3K pathway at distinct points, potential sequencing of these therapies, and the optimal sequence strategy.

Our data indicate that targeted therapy using e.g., trastuzumab deruxtecan, bicalutamide, pembrolizumab, cetuximab, entrectinib or sacituzumab govitecan might be a promising option especially for a relevant subset of patients with RM-SGC not suitable for salvage surgery. However, evidence from clinical studies regarding response rates to these therapies remains sparse, which underlines the need of multicenter clinical trials.

P1/2, N=54, Recruiting, Icahn School of Medicine at Mount Sinai | Not yet recruiting --> Recruiting

P2, N=20, Not yet recruiting, British Columbia Cancer Agency

Approximately 15% of TNBC patients have a germline mutation in BRCA1 and/or BRCA2, and for these patients, innovative therapeutic options such as olaparib and talazoparib, which are PARP inhibitors, are available. Sacituzumab govitecan (SG) is a humanized monoclonal antibody-drug conjugate directed against the surface antigen of human trophoblastic cells (Trop-2) expressed in approximately 90% of TNBC, coupled with SN-38, the active metabolite of irinotecan, a topoisomerase I inhibitor. Here, we present the case of a woman who was initially diagnosed with localized luminal B breast cancer (ER-positive; HER2-negative) and was treated with curative therapy. However, she later experienced a recurrence with metastatic TNBC (ER-negative/HER2-negative) and received treatment with sacituzumab govitecan, which resulted in prolonged disease control.

In this report we describe the case of a patient with TNBC diagnosed at the metastatic level when the primary breast tumour presented overexpression of ER end PgR. An important tumoral heterogeneity has been described in breast cancer during its natural evolution and for that reason is important to perform metastatic lesions re-biopsy, when feasible, in order to re-evaluate the biological characteristics and define the optimal therapeutic strategy.

P2, N=92, Terminated, Gilead Sciences | Active, not recruiting --> Terminated; Sponsor decision to terminate study.

Knockdown of TROP2 also resulted in decreased expression of vimentin, along with reduced migratory capacity. These findings suggest that TROP2 plays a crucial role in cSCC cell proliferation and migration, and highlight the potential of sacituzumab govitecan as a promising therapeutic option for cSCC.

P3, N=540, Recruiting, Gilead Sciences | Trial completion date: May 2027 --> Jul 2028 | Trial primary completion date: May 2027 --> Jul 2028

Pretreatment [18F]FDG PET/CT-derived biomarkers, namely TMTV and Dmax, have significant prognostic value in patients with mTNBC and HER2-low mBC treated with SG and T-DXd. These biomarkers improve prognostic prediction and may optimize treatment strategies, warranting their clinical use, but larger studies are needed to validate these findings.

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Dec 2024 --> Dec 2025

In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

SG represents a promising treatment option for Asian patients with HR+HER2- mBC (ClinicalTrials.gov identifier no. NCT04639986 ).

However, the current ADC, sacituzumab govitecan, fails to overcome the crucial role of adenosine in the suppressive immune microenvironment characteristic of this "cold tumor"...Thus, it kills tumor cells with cytotoxic drugs, comprehensively regulates immunosuppression, and restores a durable immune response. This study proposes an antibody-polymeric drug complex with immunomodulatory and immunoagonist roles, offering new insights into TNBC treatment.

Sacituzumab Govitecan (SG) is an antibody-drug conjugate (ADC) comprised of an anti-Trop-2 IgG1 molecule conjugated to SN-38, the active metabolite of irinotecan, via a pH-sensitive hydrolysable linker. The most common AEs were neutropenia, diarrhea, nausea, fatigue, alopecia, and anemia. This review outlines AE management recommendations for SG based on clinical trial protocols and Canadian guidelines, incorporating treatment delay, dose reductions, and the use of prophylactic and supportive medications.

P2, N=252, Recruiting, Guangdong Provincial People's Hospital | Initiation date: Jan 2024 --> Sep 2024

P1/2, N=76, Not yet recruiting, MedSIR